Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis
Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis
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阻断 PI3K/AKT 信号传导可抑制软骨下骨的骨硬化并减轻创伤后骨关节炎
DOI：
10.1002/jcp.26460
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发表时间：
2018-08-01
影响因子：
5.6
通讯作者：
Xian, Cory J.
中科院分区：
文献类型：
--
作者：
Lin, Chuangxin;Shao, Yan;Xian, Cory J.
PI3K/AKT 信号传导对于调节骨关节炎 (OA) 的病理生理学至关重要。然而，其在早期 OA 进展中的潜在调节作用尚未得到研究。在这里，使用小鼠胫骨不稳定 OA 模型来研究 PI3K/AKT 信号在早期软骨下骨变化和 OA 病理过程中的作用。我们发现 PI3K/AKT 信号激活显着增加，这与内侧半月板 (DMM) 不稳定后胫骨软骨下骨的异常骨形成有关，而使用 PI3K/AKT 信号抑制剂 LY294002 治疗可以有效预防这种情况。 PI3K/AKT 信号传导抑制可减轻关节软骨退化。血清和骨生化分析显示 MMP-13 水平升高，主要由软骨下骨中的成骨细胞表达。然而，LY294002 治疗减弱了这种 MMP-13 诱导。此外，PI3K/AKT 信号传导可通过激活 NF-B 通路来增强前成骨细胞增殖、分化和 MMP-13 的表达。总之，抑制 PI3K/AKT/NF-B 轴能够防止 OA 小鼠异常骨形成并减轻软骨退化。
PI3K/AKT signaling is essential in regulating pathophysiology of osteoarthritis (OA). However, its potential modulatory role in early OA progression has not been investigated yet. Here, a mouse destabilization OA model in the tibia was used to investigate roles of PI3K/AKT signaling in the early subchondral bone changes and OA pathological process. We revealed a significant increase in PI3K/AKT signaling activation which was associated with aberrant bone formation in tibial subchondral bone following destabilizing the medial meniscus (DMM), which was effectively prevented by treatment with PI3K/AKT signaling inhibitor LY294002. PI3K/AKT signaling inhibition attenuated articular cartilage degeneration. Serum and bone biochemical analyses revealed increased levels of MMP-13, which was found expressed mainly by osteoblastic cells in subchondral bone. However, this MMP-13 induction was attenuated by LY294002 treatment. Furthermore, PI3K/AKT signaling was found to enhance preosteoblast proliferation, differentiation, and expression of MMP-13 by activating NF-B pathway. In conclusion, inhibition of PI3K/AKT/NF-B axis was able to prevent aberrant bone formation and attenuate cartilage degeneration in OA mice.